The main aim of this project involves characterizing the role of the HIV envelope protein (gp120/41) in the pathogenesis of HIV disease. This effort has included biochemical and biological characterizations of the interaction between cell surface receptors and the HIV envelope. In addition we are studying the role of envelope-mediated signals in pathogenesis. We have identified a new interaction between gp120 and integrin alpha4beta7, which functions as the gut-homing receptor. Because the function of alpha4beta7 is intimately linked to gut associated lymphoid tissue, which is a principal site of HIV replication, we hypothesize that envelope-alpha4beta7 interactions play an important role in HIV pathogenesis. We have found that alpha4beta7high CD4+ T cells are more susceptible to productive infection by HIV than are alpha4beta7low-neg CD4+ T cells, in part because the former cellular subset is enriched with metabolically active cells. We determined that on these cells, alpha4beta7 appears in a complex with the CD4 receptor. We hypothesized that the specific affinity of gp120 for alpha4beta7 provides a mechanism for HIV to target metabolically active CD4+ T cells and that such an activity might prove critical for efficient virus propagation and dissemination following mucosal transmission. In addition we have investigated the interaction between HIV and alpha4beta7 on lymphocyte subsets other than CD4+ T cells. We have learned that some of the defects associated with HIV disease result from these interactions.